Depletion of major pathogenic cells in asthma by targeting CRTh2
Tao Huang, … , Cary D. Austin, Karin Reif
Tao Huang, … , Cary D. Austin, Karin Reif
Published May 19, 2016
Citation Information: JCI Insight. 2016;1(7):e86689. https://doi.org/10.1172/jci.insight.86689.
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Categories: Research Article Immunology Therapeutics

Depletion of major pathogenic cells in asthma by targeting CRTh2

Abstract

Eosinophilic inflammation and Th2 cytokine production are central to the pathogenesis of asthma. Agents that target either eosinophils or single Th2 cytokines have shown benefits in subsets of biomarker-positive patients. More broadly effective treatment or disease-modifying effects may be achieved by eliminating more than one inflammatory stimulator. Here we present a strategy to concomitantly deplete Th2 T cells, eosinophils, basophils, and type-2 innate lymphoid cells (ILC2s) by generating monoclonal antibodies with enhanced effector function (19A2) that target CRTh2 present on all 4 cell types. Using human CRTh2 (hCRTh2) transgenic mice that mimic the expression pattern of hCRTh2 on innate immune cells but not Th2 cells, we demonstrate that anti-hCRTh2 antibodies specifically eliminate hCRTh2+ basophils, eosinophils, and ILC2s from lung and lymphoid organs in models of asthma and Nippostrongylus brasiliensis infection. Innate cell depletion was accompanied by a decrease of several Th2 cytokines and chemokines. hCRTh2-specific antibodies were also active on human Th2 cells in vivo in a human Th2-PBMC-SCID mouse model. We developed humanized hCRTh2-specific antibodies that potently induce antibody-dependent cell cytotoxicity (ADCC) of primary human eosinophils and basophils and replicated the in vivo depletion capacity of their murine parent. Therefore, depletion of hCRTh2+ basophils, eosinophils, ILC2, and Th2 cells with h19A2 hCRTh2–specific antibodies may be a novel and more efficacious treatment for asthma.

Authors

Tao Huang, Meredith Hazen, Yonglei Shang, Meijuan Zhou, Xiumin Wu, Donghong Yan, Zhonghua Lin, Margaret Solon, Elizabeth Luis, Hai Ngu, Yongchang Shi, Arna Katewa, David F. Choy, Nandhini Ramamoorthi, Erick R. Castellanos, Mercedesz Balazs, Min Xu, Wyne P. Lee, Marissa L. Matsumoto, Jian Payandeh, Joseph R. Arron, Jo-Anne Hongo, Jianyong Wang, Isidro Hötzel, Cary D. Austin, Karin Reif

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Figure 1

CRTh2 is expressed on human type-2 immune cells and CRTh2+ memory CD4+ T cells are the major producers of CD4+ T cell–derived Th2 cytokines.

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CRTh2 is expressed on human type-2 immune cells and CRTh2+ memory CD4+ T...
(A) CRTh2 expression was assessed on human leukocyte populations and in vitro–polarized Th cells by flow cytometry with anti-CRTh2 Abs (clone BM16, black line) compared with isotype control Ab (gray line). (B) Expression of CRTh2 in human tissues was examined by IHC using rabbit anti-hCRTh2 mAb (clone 81.12.4) and, for comparison, an isotype control antibody. (C) Graphs show levels of Th2 (IL4, IL5, IL13, IL9) and Th1/Th17 (IFNG, IL17A, TNFA, GMCSF) cytokine production in supernatants of CRTh2+CD45RO+ and CRTh2−CD45RO+ memory CD4+ T cells. T cell subsets were sorted by flow cytometry from human PBMCs, and equal numbers were stimulated with anti-CD3 and anti-CD28 antibodies for 48 hours at 37°C. (A–C) Data shown are representative of at least 2 independent experiments. PBMC, peripheral blood mononuclear cell.